ISIS Penning source extraction studies reveal the 3-dimensional Child-Langmuir effect.

The standard 1X ISIS negative Penning surface plasma source has reliably produced an H- beam for ISIS operations for 35 years. In order to meet the 60 mA, 2 ms, and 50 Hz beam current and duty cycle required for the front end test stand (Letchford et al., in Proceedings of IPAC2015, Richmond, VA, USA, 2015), a 2X scaled source has been developed [Faircloth et al., AIP Conf. Proc. 2052, 050004 (2018)]. The 2X source has a plasma chamber twice the linear dimensions of the 1X source. This paper investigates the comparison between different emission areas (plasma electrode aperture dimensions) for both the 1X and 2X sources. Slit and circular extraction schemes are studied. A 3D Child-Langmuir relationship is observed where the space charge limited current density depends on the aspect ratio of the extraction aperture.

Prolonged morphine treatment alters δ opioid receptor post-internalization trafficking.

BACKGROUND AND PURPOSE: The δ opioid receptor (DOP receptor) undergoes internalization both constitutively and in response to agonists. Previous work has shown that DOP receptors traffic from intracellular compartments to neuronal cell membranes following prolonged morphine treatment. Here, we examined the effects of prolonged morphine treatment on the post-internalization trafficking of DOP receptors. EXPERIMENTAL APPROACH: Using primary cultures of dorsal root ganglia neurons, we measured the co-localization of endogenous DOP receptors with post-endocytic compartments following both prolonged and acute agonist treatments. KEY RESULTS: A departure from the constitutive trafficking pathway was observed following acute DOP receptor agonist-induced internalization by deltorphin II. That is, the DOP receptor underwent distinct agonist-induced post-endocytic sorting. Following prolonged morphine treatment, constitutive DOP receptor trafficking was augmented. SNC80 following prolonged morphine treatment also caused non-constitutive DOP receptor agonist-induced post-endocytic sorting. The µ opioid receptor (MOP receptor) agonist DAMGO induced DOP receptor internalization and trafficking following prolonged morphine treatment. Finally, all of the alterations to DOP receptor trafficking induced by both DOP and MOP receptor agonists were inhibited or absent when those agonists were co-administered with a DOP receptor antagonist, SDM-25N. CONCLUSIONS AND IMPLICATIONS: The results support the hypothesis that prolonged morphine treatment induces the formation of MOP-DOP receptor interactions and subsequent augmentation of the available cell surface DOP receptors, at least some of which are in the form of a MOP/DOP receptor species. The pharmacology and trafficking of this species appear to be unique compared to those of its individual constituents. LINKED ARTICLES: This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.

Anti-nociception mediated by a κ opioid receptor agonist is blocked by a δ receptor agonist.

BACKGROUND AND PURPOSE: The opioid receptor family comprises four structurally homologous but functionally distinct sub-groups, the µ (MOP), δ (DOP), κ (KOP) and nociceptin (NOP) receptors. As most opioid agonists are selective but not specific, a broad spectrum of behaviours due to activation of different opioid receptors is expected. In this study, we examine whether other opioid receptor systems influenced KOP-mediated antinociception. EXPERIMENTAL APPROACH: We used a tail withdrawal assay in C57Bl/6 mice to assay the antinociceptive effect of systemically administered opioid agonists with varying selectivity at KOP receptors. Pharmacological and genetic approaches were used to analyse the interactions of the other opioid receptors in modulating KOP-mediated antinociception. KEY RESULTS: Etorphine, a potent agonist at all four opioid receptors, was not anti-nociceptive in MOP knockout (KO) mice, although etorphine is an efficacious KOP receptor agonist and specific KOP receptor agonists remain analgesic in MOP KO mice. As KOP receptor agonists are aversive, we considered KOP-mediated antinociception might be a form of stress-induced analgesia that is blocked by the anxiolytic effects of DOP receptor agonists. In support of this hypothesis, pretreatment with the DOP antagonist, naltrindole (10 mg·kg(-1) ), unmasked etorphine (3 mg·kg(-1) ) antinociception in MOP KO mice. Further, in wild-type mice, KOP-mediated antinociception by systemic U50,488H (10 mg·kg(-1) ) was blocked by pretreatment with the DOP agonist SNC80 (5 mg·kg(-1) ) and diazepam (1 mg·kg(-1) ). CONCLUSIONS AND IMPLICATIONS: Systemic DOP receptor agonists blocked systemic KOP antinociception, and these results identify DOP receptor agonists as potential agents for reversing stress-driven addictive and depressive behaviours mediated through KOP receptor activation. LINKED ARTICLES: This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.

Supramolecular interactions in PuO2Cl4(2-) and PuCl6(2-) complexes with protonated pyridines: synthesis, crystal structures, and Raman spectroscopy.

The synthesis, crystal structures, and Raman spectra of seven plutonium chloride compounds are presented. The materials are based upon Pu(VI)O2Cl4(2-) and Pu(IV)Cl6(2-) anions that are charge balanced by protonated pyridinium cations. The single crystal X-ray structures show a variety of donor-acceptor interactions between the plutonium perhalo anions and the cationic pyridine groups. Complementary Raman spectra show that these interactions can be probed through the symmetric vibrational mode of the plutonyl moiety. Unlike previously reported studies in similar uranyl(VI) systems, the facile redox chemistry of plutonium in aqueous solution has demonstrated the feasibility of using not only the An(VI)O2Cl4(2-) anion with approximate D4h symmetry but also the approximately Oh An(IV)Cl6(2-) anion in order to manipulate both the structure and dimensionality of such hybrid materials.

Augmenting cognitive behaviour therapy for post-traumatic stress disorder with emotion tolerance training: a randomized controlled trial.

BACKGROUND: Many patients do not adhere to or benefit from cognitive behaviour therapy (CBT) for post-traumatic stress disorder (PTSD). This randomized controlled trial evaluates the extent to which preparing patients with emotion regulation skills prior to CBT enhances treatment outcome. METHOD: A total of 70 adult civilian patients with PTSD were randomized to 12 sessions of either supportive counselling followed by CBT (Support/CBT) or emotion regulation training followed by CBT (Skills/CBT). RESULTS: Skills/CBT resulted in fewer treatment drop-outs, less PTSD and anxiety, and fewer negative appraisals at 6 months follow-up than Support/CBT. Between-condition effect size was moderate for PTSD severity (0.43, 95% confidence interval x0.04 to 0.90). More Skills/CBT (31%) patients achieved high end-state functioning at follow-up than patients in Support/CBT (12%) [Χ2(n=70)=3.67, p<0.05]. CONCLUSIONS: This evidence suggests that response to CBT may be enhanced in PTSD patients by preparing them with emotion regulation skills. High attrition of participants during the study limits conclusions from this study.

Structural studies coupling X-ray diffraction and high-energy X-ray scattering in the UO2(2+)-HBr(aq) system.

The structural chemistry of uranium(VI) in concentrated aqueous hydrobromic acid solutions was investigated using both single crystal X-ray diffraction and synchrotron-based high-energy X-ray scattering (HEXS) to reveal the structure of the uranium(VI) complexes in solution prior to crystallization. The crystal structures of a series of uranyl tetrabromide salts are reported, including Cs(2)UO(2)Br(4), Rb(2)UO(2)Br(4)·2H(2)O, K(2)UO(2)Br(4)·2H(2)O, and (NH(4))(2)UO(2)Br(4)·2H(2)O, as well as a molecular dimer of uranium(VI), (UO(2))(2)(OH)(2)Br(2)(H(2)O)(4). Limited correspondence exists between the structures observed in the solid state and those in solution. Quantitative analysis of the HEXS data show an average U-Br coordination number of 1.9(2) in solution, in contrast to the U-Br coordination number of 4 in the solid salts.

A computerized system for reporting medication events in psychiatry: the first two years of operation.

The aim of this paper is to describe the first 2 years of operation of an electronic system for reporting medication events in psychiatry (Medi-Event system). We have carried out a descriptive analysis of all medication events (errors, near misses and adverse drug reactions) reported between 1 March 2008 and 28 February 2010 at a large, specialist UK psychiatric hospital. A total of 406 medication errors, 40 near misses and no adverse drug reactions were reported in the study period, representing a very large increase in reporting frequency with respect to the previous paper system. The majority (88.8%) of incidents were medication administration errors. The most common error types were failure to sign for a drug and omission of a drug without valid clinical reason. Although most errors were of minor severity, 6.3% were rated as moderate or serious. Distraction was cited as the most common contributory factor, also poor communication and being unfamiliar with the ward. In conclusion, use of the Medi-Event system increased the reporting of medication errors. Analysis of the pattern of errors, as well as of contributory factors and suggestions for error prevention, may help reduce the frequency of medication events and hence improve patient care.

Tactile sensory and pain networks in the human spinal cord and brain stem mapped by means of functional MR imaging.

BACKGROUND AND PURPOSE: Touch and brush sensory stimuli elicit activity in discriminative touch pathways involving specific regions in the spinal cord and brain stem. However, no study has mapped normal sensory activity noninvasively in healthy humans. The purpose of this study is to map the neuronal activity of sensory input to understand abnormal sensory transmission. MATERIALS AND METHODS: In the present study, spinal fMRI (by using SEEP) was used to map the activity involved with light touch (2 g and 15 g von Frey filaments) and brush stimuli in the brain stem and spinal cords of 8 healthy volunteers. The results were spatially normalized and analyzed with custom-made software. Areas of SEEP activity were identified by using general linear model analysis. RESULTS: The 2 g von Frey filament showed predominant activity in the medulla around the ipsilateral dorsal gracile and cuneate nuclei. The 15 g filament elicited significant activity in the ipsilateral dorsal and contralateral ventral gray matter areas of the spinal cord, areas around the olivary nuclei, pontine reticular formation, periaqueductal gray, and raphe nuclei in the rostral pons and midbrain. The brush stimuli elicited more activity in the medulla around the ipsilateral cuneate and gracile nuclei. CONCLUSIONS: The 2 g filament and brush stimuli activated areas associated with a touch response. The 15 g filament activated areas associated with a pain response. The results from this study identify specific neuronal regions in the brain stem and spinal cord involved in sensory transmission and help understand altered sensory and pain states.

Low doses of alpha 2-adrenoceptor antagonists augment spinal morphine analgesia and inhibit development of acute and chronic tolerance.

BACKGROUND AND PURPOSE: Ultra-low doses of opioid receptor antagonists augment spinal morphine antinociception and block the induction of tolerance. Considering the evidence demonstrating functional and physical interactions between the opioid and alpha(2)-adrenoceptors, this study investigated whether ultra-low doses of alpha(2)-adrenoceptor antagonists also influence spinal morphine analgesia and tolerance. EXPERIMENTAL APPROACH: Effects of low doses of the competitive alpha(2)-adrenoceptor antagonists-atipamezole (0.08, 0.8 ng), yohimbine (0.02, 2 ng), mirtazapine (0.02 ng) and idazoxan (0.08 ng) were investigated on intrathecal morphine analgesia, as well as acute and chronic morphine antinociceptive tolerance using the rat tail flick and paw pressure tests. KEY RESULTS: At doses markedly lower than those producing alpha(2)-adrenoceptor blockade, atipamezole, yohimbine, mirtazapine and idazoxan, prolonged the antinociceptive effects of morphine. When co-administered with repeated acute spinal injections of morphine, all four agents blocked the induction of acute tolerance. Co-injection of atipamezole with morphine for 5 days inhibited the development of tolerance in a chronic treatment paradigm. Spinal administration of atipamezole also reversed established antinociceptive tolerance to morphine as indicated by the restoration of morphine antinociceptive potency. The effects of atipamezole on spinal morphine tolerance were not influenced by treatment with 6-hydroxydopamine. CONCLUSIONS AND IMPLICATIONS: Low doses of competitive alpha(2)-adrenoceptor antagonists can augment acute morphine analgesia and block or reverse tolerance to spinal administration of morphine. These actions are interpreted in terms of their interaction with an opioid-alpha(2)-adrenoceptor complex, whose activity may have a function in the genesis of analgesic tolerance.

The changing face of bipolar disorder: adolescence to adulthood.

Over the past decade, there has been greater acceptance of the existence of bipolar disorder (BD) in adolescents. The onset of BD during this period severely affects the acquisition of key developmental skills. Debate around diagnosis, comorbidity and treatment is strong and little is known about the long-term impact BD has on an adolescents as they approach adulthood, from both illness and functional perspectives. A review of psychological and medical databases using the search terms ''adolescent onset'', ''pediatric onset'', ''juvenile onset'', ''bipolar disorder'', ''course'' and ''outcome'' was conducted. Emphasis was placed on the information available from studies, which have described the outcome of adolescent onset BD either prospectively, retrospectively, or both. Twelve studies were identified that focused on the long-term course of adolescent onset BD. Findings on the course and outcomes are conflicting. These studies are from few centres or research groups and have small sample sizes, varied methodologies and relatively brief follow-up durations. There are few studies available on the course and outcome of adolescent onset BD. Although there seems to be less controversy in this age group compared to the prepubertal age group, there remains a need for prospective studies of large systematically ascertained samples.

Sensory neuron and substance P involvement in symptoms of a zymosan-induced rat model of acute bowel inflammation.

Intestinal inflammation is a painful syndrome with multiple symptoms, including chronic pain. This study examined the possible role of sensory neurons and substance P in symptoms of an animal model of acute intestinal inflammation. The model was induced by injecting ethanol and zymosan into the colon of anesthetized male rats. Three hours later, sections of the colon were stained with hematoxylin and eosin. To determine the role of substance P, 5 mg/kg of the neurokinin-1 receptor (NK-1r) antagonist, CP-96,345, or 300 microg/kg of an antisense oligonucleotide targeted at NK-1r mRNA was administered. Spinal cord sections were examined for internalization of NK-1r, as an indicator of substance P release. Sections of colon revealed infiltration of inflammatory cells following ethanol and zymosan treatment. Plasma extravasation in rats given ethanol and zymosan was significantly greater than in controls given saline only (P<0.0001) or saline and ethanol (P<0.001). In ethanol- and zymosan-treated rats given CP-96,345, plasma extravasation was significantly less than in rats given ethanol and zymosan without the antagonist (P<0.0001). Administration of the antisense oligonucleotide also resulted in lower levels of plasma extravasation compared with controls (P<0.01). Internalization of the NK-1r was observed in neurons of lamina I in the T13-L2 and L6-S2 regions of the spinal cord, as well as in sympathetic preganglionic neurons at the L1 level. This internalization was observed in the absence of any other stimulus besides the inflammation itself. This study implicates substance P and its receptor, the NK-1r, in acute inflammation of the colon.

Morphine priming in rats with chronic inflammation reveals a dichotomy between antihyperalgesic and antinociceptive properties of deltorphin.

We previously showed that prolonged morphine treatment and chronic inflammation both enhanced delta opioid receptor (deltaOR) cell surface density in lumbar spinal cord neurons. Here, we sought to determine whether administration of morphine to rats with chronic inflammation would further increase the bio-availability of deltaOR, and thereby the analgesic properties of the deltaOR agonist deltorphin, over that produced by inflammation alone. We found that chronic inflammation produced by injection of complete Freund's adjuvant (CFA) into the hind paw resulted in a bilateral increase in the binding and internalization of fluorescent deltorphin in neurons of the lumbar spinal cord as did prolonged morphine treatment [Morinville A, Cahill CM, Aibak H, Rymar VV, Pradhan A, Hoffert C, Mennicken F, Stroh T, Sadikot AF, O'Donnell D, Clarke PB, Collier B, Henry JL, Vincent JP, Beaudet A (2004a) Morphine-induced changes in delta opioid receptor trafficking are linked to somatosensory processing in the rat spinal cord. J Neurosci 24:5549-5559]. This effect was accompanied by an increase in the antinociceptive efficacy of intrathecal deltorphin as measured using the tail-flick test. Treatment of CFA-injected rats with morphine decreased the cell surface availability of deltaOR in neurons of the dorsal horn of the lumbar spinal cord as compared with treatment with CFA alone. Behaviorally, it significantly enhanced the antihyperalgesic effects of deltorphin (plantar test; % maximum possible antihyperalgesic effect (MPAHE)=113.5%+/-32.4% versus 26.1%+/-11.6% in rats injected with CFA alone) but strongly reduced the antinociceptive efficacy of the drug (tail-flick test; % maximum possible antinociceptive effect (MPE)=29.6%+/-3.6% versus 66.6%+/-6.3% in rats injected with CFA alone) suggesting that the latter, but not the former, is linked to the deltaOR trafficking events observed neuroanatomically. These results demonstrate that in chronic inflammation, the antihyperalgesic effects of deltaOR agonists may be enhanced by morphine pre-treatment. They also reveal a dichotomy between mechanisms underlying antihyperalgesic and antinociceptive effects of deltaOR agonists.

Scale matters: the need for a Bipolar Depression Rating Scale (BDRS).

OBJECTIVE: To briefly review the clinical and biological distinctions between unipolar and bipolar depression critiquing in particular currently available depression rating scales and discuss the need for a new observer-rated scale tailored to bipolar depression. METHOD: Relevant literature pertaining to the symptomatic differences between bipolar disorder and unipolar disorder as well as their measurement using existing assessment scales was identified by computerized searches and reviews of scientific journals known to the authors. RESULTS: Bipolar depression is distinct from unipolar depression in terms of phenomenology and clinical characteristics. These distinguishing features can be used to identify bipolarity in patients that present with recurrent depressive episodes. This is important because current self-report and observer-rated scales are optimized for unipolar depression, and hence limited in their ability to accurately assess bipolar depression. CONCLUSION: The development of a specific bipolar depression rating scale will improve the assessment of bipolar depression in both research and clinical settings and assist the development of better treatments and interventions.

Interactions of poly(amino acids) in aqueous solution with charged model surfaces--analysis by colloidal probe.

Biomolecules in a confined solution environment may be subject to electrostatic forces with a range up to 100 nm, while van der Waals interaction will account for shorter-range forces. The response of two model poly(amino acids)--poly-L-lysine and poly-L-glutamic acid--has been investigated for a silica/Si-oxide surface at pH 6. The model amino acids were adsorbed, or covalently coupled, to colloidal probes consisting of a microsphere attached to a force-sensing lever. The methodology was based on sensing interaction between the probe and a flat surface through carrying out force versus distance analysis with a scanning force microscope. The results were analyzed within the framework of the conventional DLVO theory. The outcomes illustrate both repulsive and attractive long-range interactions that will hinder, or promote, colloidal biospecies in solution entering the region of attractive short-range interactions at the physical interface. Large 'snap-on' distances were observed for some systems and have been ascribed to compression of the 'soft' functionalized layers. Those observations and measurements of adhesion provided insight into conformation of the adsorbed species and strength of attachment. The results have implications for the efficacy of methods and devices that seek to exploit the properties of micro/nano-fluidic systems.

Rationalizing radio medical advice for maritime emergencies.

The provision of radio medical advice by the National Health Service for British coastal waters has developed in an ad hoc fashion. In 1999, the closure of one of the two centres providing such advice led to unexpected problems. The demographic characteristics of the offshore population covered by each centre were markedly different and this resulted in a different spectrum of medical emergencies presenting to the sole remaining centre. Subsequent data collection of the details of medical emergencies presenting from offshore allowed an audit to inform the development of training packages for both base and remote practitioners. This has led to an ongoing national rationalization of ship-to-shore radio medical advice for the UK.